Disclaimer statement
International Standards
IAEA- US – Canada
The professional opinions I express today, and
the mention or display of any commercial
products, is neither an endorsement nor
necessarily reflect the official position of the Food
and Drug Administration or the Department of
Health and Human Services.
August 4, 2011
American Association of Physicists in Medicine
Vancouver, British Columbia, Canada
Orhan H Suleiman MS PhD, FAAPM
Senior Science Policy Adviser
Office of New Drugs (ODEIV)
Center for Drug Evaluation and Research
1
How standards evolve.
• Education - professional forums,
publications…..
• Consensus for Good Practice
• Voluntary Standards
• Mandatory Standards (Regulations)
• Enforcement.
• Litigation (regulator of last resort).
2
How do regulatory standards work
internationally?
• No different than they work within the
United States!
• A patchwork of voluntary and mandatory
standards among different jurisdictions.
1
Science and public health is often the
foundation upon which such
regulatory policy is based.
• International Organizations (IAEA, ICRP,
ICRU, IEC, ISO, UNSCEAR)
• National Organizations (non- US)
• NCRP, NRC, CRCPD, FDA (Health
Canada, GSF, NRPB, etc.)
Each agency has it’s own rules.
• Voluntary standards (guidance, “should”,
lack enforcement)
• Mandatory regulations
– Often promulgated based on legal
requirements
– Most government agencies have an open
process of rulemaking. Federal rulemaking:
• Proposed notice of intent for rulemaking
• Proposed rule with public comment period
• Final rule
States and Other Agencies
• Conference of Radiation Control Program
Directors
• Organization of Agreement States
• State and local municipalities
• Counties
• Territories
Not all processes are open!
• Many professional and industrial organizations limit
discussion only to their membership or committees.
• Some even restrict access to their final reports unless
purchased.
• However, there has been an effort for free access, e.g.
NAS* allows free pdf internet downloads (by chapter);
and in recent years the ICRP has allowed public
comments on its draft documents.
*National Academy of Sciences
2
In the United States there are many ways
to educate and regulate via standards:
• Reimbursement standards
– Centers for Medicare and Medicaid Services (CMS)“reasonable and customary”
– Insurance Companies
Effective dose, E, despite limitations, is a
valuable dose standard, but has been
adopted very slowly in the United States!
• Product Standards
– Food an Drug Administration (FDA)- “safety and efficacy”
– Testing Laboratories
A more perfect metric would also adjust
each organ dose for age, sex, and other
dose modifying factors such as dose rate.
• Professional standards
– Licensing/ Registration (States)
– Certification (Professional Boards)
– Accreditation
• Joint Commission on the Accreditation of Healthcare
Organizations (JCAHO)
• American College of Radiology (ACR)
NASA and NCI have models that do this.
Tissue Weighting Factors (w t)
Organ (Tissue) Reports: 26 60 DRAFT/103
Gonads
Breast
Red BM, lung
Thyroid
Bone surfaces
Colon, stomach (NC- not
calculated)
Bladder, liver, esophagus
Skin
Salivary glands, brain
Remainder
Total
0.25
0.15
0.12
0.03
0.03
NC
0.20 0.05/0.08
0.05
0.12
0.12
0.12
0.05 0.05/0.04
0.01
0.01
0.12
0.12
NC
NC
NC
0.30
1.00
0.05 0.05/0.04
0.01
0.01
NC
0.01
0.05 0.10/0.12
1.00
1.00
Patchwork process of promulgating standards
in the US has been problematic!
1975
1977
1980’s
1991
1991
1993
2004
2008
2009
11
FDA’s RDRC* Dose limits- rem
ICRP* promulgates effective dose equivalent, H.
R to air kerma, rad to Gy; rem to Sv; mCi to MBq.
NRC** adopts H for radiation dose
ICRP replaces H with effective dose, E.
NCRP*** adopts E.
ICRP proposes new w t’’s, modifying how E is
calculated.
ICRP adopts new w t ’s.
NRC considers adopting E
*Radioactive Drug Research Committee (CFR 21 361.1)
*International Commission on Radiological Protection
**Nuclear Regulatory Commission
*** National Council on Radiation Protection and Measurements
3
FDA regulates most medical products
(FDA consists of many Centers)
• Center for Drug Evaluation and Research (CDER) –
Radiopharmaceuticals
Center for Devices and
Radiological Health
Authority to regulate electronic and medical
radiation products under 3 separate statutes
• Center for Devices and Radiological Health* (CDRH) –
X-ray, medical devices, accelerators, brachytherapy
sources, imaging technologies
• Radiation emitting electronic products- includes
consumer, non-medical electronic products.
• Center for Biologics Evaluation and Research (CBER) –
Blood Irradiators
• Medical Devices
• Center for Food Safety and Nutrition* (CFSAN) – Food
irradiators
• Mammography
Radiation Emitting Electronic Products
(Radiation Control for Health and
Safety Act of 1968)*
•
•
•
•
Mandatory Emission Performance Standards
Consumer and Medical Products
Microwave ovens, lasers
X-rays (medical and security products)
* Center for Devices and Radiological Health
Medical Device Act of 1976*
• 510 (k) – predicate device, substantial
equivalency
• Class I – Minimal controls
• Class II- Special controls
• Class III
– High risk devices
– May require clinical trials for premarket
approval (PMA).
– *Center for Devices and Radiological Health
4
– Chest
– Abdomen/Spine
– Mammography
– CT
– Fluoroscopy
16
13
Mean Glandular Dose
Phantom Score
(w/o artifact subtraction)
14
12
12
11
10
10
8
9
6
8
4
7
2
6
0
1970
Phantom Score
• Collaborative federal/state program which
conducts surveys of patient dose from
several diagnostic x-ray imaging exams
Dose and Image Quality Trends in Mammography
Dose (mGy)
Nationwide Evaluation of X-ray
Trends (NEXT)
5
1975
1980
1985
1990
1995
2000
2005
Year
In order to detect change clinically, you need to assure
the standard image remains constant.
Mammography Quality Standards Act
of 1992*
• Assures quality by establishing
standards and regulating:
– Quality control of equipment
– Personnel
– Image quality (Imaging and dosimetry
phantom)
* Center for Devices and Radiological Health
5
How are radiolabeled drugs regulated by
FDA’s Center for Drug Evaluation and
Research?
Basic Research:
Radioactive Drug Research Committee (nonIND human research, not for diagnostic, therapeutic,
safety, or efficacy)
• Formally codified in 21 CFR 361.1 (1975)
• Allows human research with radioactive drugs without an
IND:
– Research must be basic
– RDRC must review and approve protocol
– There is no clinically detectable pharmacologic effect
from the administered drug
– and radiation dose limits are met
Medical Isotopes
(Radiopharmaceuticals)
• Center for Drug Evaluation and Research (CDER)
• Center for Biologics Evaluation and Research
(CBER)
What does it take to get a drug
approved?
Research Phase
• Clinical Research under an Investigational New
Drug (IND) Application
– Phase I- Safety “n ~ 20 – 80”
– Phase II- Efficacy “n < several hundred”
– Phase III- Large scale studies for benefit –
risk, dosing, and physician labeling
information “n ~ several hundred to several
thousand”
6
What does it take to get a drug
approved?- Application process – New
Drug Application
• NDA Process:
http://www.fda.gov/cder/regulatory/
applications/nda.htm#Related%20Topics:
• Application Fee for NDA ~ $1 M
•
Can only be used for FDA approved, or
exempt, medical products.
Human research (with an approved or
unapproved medical product) must be
conducted under an:
–
–
-
• Quality and purity of product
Good Manufacturing Practice (GMP) and
Chemistry Manufacturing Control (CMC)
+
Off-Label Use
•
What does it take to get a drug
approved?
Manufacturing Standards
IND for radiolabeled drugs, or
an RDRC for radiolabeled drugs;
or an IDE for medical devices.
There is no such thing as off-label use for an
unapproved, uncleared, unlicensed medical
product.
Manufacturing Responsibilities
Pharmaceuticals: Good Manufacturing Practice (GMP) – 21
CFR Parts 210, 211, 212 (proposed), 600-680
Medical Devices: Quality System (QS) regulations – 21
CFR Part 820
Guidance for Industry and FDA Current Good
Manufacturing Practice for Combination Products
http://www.fda.gov/cder/guidance/OCLove1dft.htm
7
Licensing
• FDA does not license radioactive materials
• Radioactive materials licensed by the Nuclear
Regulatory Commission (NRC) or
• Radioactive materials licensed by Agreement States (36
states with formal “agreements” with the NRC
• FDA approves biological products by via the Biological
Licensing Application (BLA)
• FDA approves radiolabeled drugs via the New Drug
Application (NDA)
•
Current Global Issues
• Patient Release Criteria
• Global Molybdenum 99 shortage
• Deterministic effects from imaging exams
www.fda.gov/cder/guidance/5645fnl.htm
Patient release criteria (1)
Patient release criteria (2)
30 mCi rule – a simple practical rule, but ignored
the fact that doses would vary based on each
radiolabeled drug.
In 1997 NRC shifted to dose limits for general
public (1 mSV), caregivers (5 mSv), and certain
family members for specific circumstances.
Often required overnight stay, or…
Therapeutic doses were administered in 30 mCi
“fractions”, but unlike external beam therapy,
fractionation was not factored into the patient
dose calculation!
30 mCi rule still impacts on practice of medicine
in some countries and states, requiring overnight
hospitalization or limiting administered activity.
Practice still varies worldwide, and remains
controversial even in the U.S.
8
Molybdenum shortage
(Global interdependency)
• Canadian Maple Reactors were to replace aging
Chalk River Reactor, but were never licensed
due to design flaws.
• When Chalk River went offline, worldwide
shortage ensued.
• Patchwork network of reactors from Europe,
Australia, South Africa, maintained the supply,
despite lack of what I perceived was a
coordinated response.
Patient radiation safety
Fluoro Skin necrosis
CT hair loss
Cardiac damage?
Many voluntary educational initiatives
•
•
•
•
•
•
•
NEMA Dose Check standard
Image Gently and Image Wisely campaigns
Improving patient awareness
Encouraging appropriate use criteria (AUC)
AAPM CT Summit
FDA Radiation Dose Initiative
Exam recordkeeping (IAEA smart card, historical
FDA patient record card)
http://www.imagewisely.org/Patients.aspx
9
How do we protect patients?
Should we be concerned about multiple
exams, including nuclear medicine doses?
• Cardiac risk is a known non-cancer risk associated with
radiation.
• Some patients have received as many as 15 multi
modality imaging exams*.
• Unlike x-ray, highest doses are not skin doses, but
internal organs, and not detected.
• Mean nuclear medicine doses are twice the mean CT
dose (ICRP Report 160).
» American College of Cardiology (New Orleans, April, 2011)
Why aren’t we seeing deterministic effects
from nuclear medicine procedures?
• Highest dose to internal organs, not visible.
• Additive and delayed effects may not occur for
days, weeks, or months.
• Cardiac damage from radiation difficult to
differentiate from patients who may have cardiac
disease and are the ones imaged.
• Dicentric analysis for radiation dose not a common
test procedure (0.25 Sv threshold), but has been
observed in cardiac fluoroscopy patients.
Mean Dose per Patient in the United States
(395 million total exams)
•
Nuclear Medicine*
~ 18** million exams (4.5% of exams, 26% of collective dose)
12.8 mSv/patient (1st)
85% of dose from cardiac procedures
•
Interventional Fl*
53 % of dose from cardiac procedures
•
Computed Tomography (CT)*
~ 17** million exams (4.3 % of exams, 14% of collective dose)
7.5 mSv/patient (2nd)
~ 67** million exams (17 % of exams, 49% of collective dose)
6.6 mSv/patient (3rd)
49% of dose from abdomen/pelvis procedures
•
Conventional R/F
–
–
~ 293** million exams (74% of exams, 11% of collective dose)
0.34 mSv/patient (4th)
*High dose procedures performed with drug imaging agent.
** NCRP Report 160 Ionizing radiation Exposure of the Population of the United States (2009)
Dicentric Analysis is a potential tool to verify
radiation effects from radiological procedures
TRICENTRIC / DICENTRICS / ACENTRICS
Gordon K. Livingston, Ph.D. REAC/TS, ORISE & ORAU, Oak Ridge, TN
10
In closing…..
• Although it is essential for qualified
personnel to operate these technologies,
and we need to assure such qualifications
exist …
• One simple technical solution would be
modality independent dose display and
recordkeeping.
• IAEA Smart Card
• A movement in the U.S. for standardized
medical records, including
• recording radiation dose from “high dose
diagnostic procedures”
Organ dose standardization now
exists for all modalities
We need to move on to the next logical step,
standardized dose display and recording.
Originally developed for the nuclear medicine community
in the 1960’s by the Medical Internal Radiation Dosimetry
(MIRD) committee of the Society of Nuclear Medicine and
Oak Ridge National Lab. It was adapted for x-ray in the
70’s (FDA), and CT (NRPB) in the 90’s. This capability
now exists in many countries and universities.
• Modality specific “dose” exists:
– Air kerma, kerma area product for fluoroscopy
– CTDI* for CT
– MBq (mCi) administered activity in nuclear medicine
• Whole body dose, and dose derivatives can now
be calculated, for standard patients of different
sizes.
• Has this idea been discussed globally?
Today, many patient models exist, from infants to adults
(Dose requires a patient of known size!)
This concept is the scientific basis for radiation risk
assessment today and can be calculated for all
modalities.
We have:
43
11
FDA
10903 New Hampshire Ave
Silver Spring, Maryland 20993
12